Preparation of polymers

ABSTRACT

BIODEGRADABLE AMINOTRIAZOLE POLYMERS WHICH ARE PRODUCED FROM DIHYDRAZIDES ARE DISCLOSED.

United States Patent O 3,809,683 PREPARATION OF POLYMERS Edward EmilSchmitt, Norwalk, Conn., and Rocco Albert Polistina, Port Chester, N.Y.,assignors to American Cyanamid Company, Stamford, Conn. No Drawing.Filed Feb. 16, 1973, Ser. No. 333,432 Int. Cl. C08g 33/04 U.S. Cl.260-78.4 N 7 Claims ABSTRACT OF THE DISCLOSURE Biodegradableaminotriazole polymers which are produced from dihydrazides aredisclosed.

BACKGROUND OF THE INVENTION The production of polymeric materials whichare biodegradable i.e. they can be decomposed by biological action,within 1 year after implantation has recently become of increasedimportance. These polymers are useful for many applications, especiallyin the medical field where biodegradability is required. For example, inthe treatment of minor or major wounds, sutures which degrade after arelatively short time are more advantageous, especially in regard tosubdermal suturing.

Homopolymers of aliphatic dihydrazides are known to those skilled in theart, see, for example, U.S. 2,512,667. The lower members of the seriesare readily soluble in water and quite sensitive to moisture. Thehomopolymers which contain longer aliphatic members are water-insolubleand are therefore more applicable to fabrication into films or fibers.Because of our interest in biodegradable materials we tested this latterclass of homopolymers for this property and found that, in general, theywere inert to tissue degrading mechanisms at least during the first 6months after implantation.

SUMMARY We have now discovered a unique class of water-insolublecopolyaminotriazoles which can be formed into physically stable (beforeimplantation) films, molded objects, fibers etc. which are biodegradablewithin a reasonable period of time (3-6 months). Thesepolyaminotriazoles possess a desirable hydrophobic/hydrophilic balancewhich permits fabrication and storage stability but possess enoughaffinity for the body fluids to permit eventual biodegradation. Thisbalance has been found to exist only when the nitrogen content of thisspecific class of polymers falls within the range of 31.5 to 35.5% byweight. They may be used as films in the topical treatment of burns etc.or as a surgical element during the course of an operation or in thetemporary placement of organs.

DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTS Asmentioned briefly above, we have now found that a certain group ofpolyarninotriazoles are biodegradable and therefore are especiallyattractive for use in the medical and agricultural fields.

The novel polymers of our invention have the general where x is -6,inclusive, y is 6-18, inclusive, the nitrogen content of the polymerranges from about 31.5% to about 35.5 by weight, based on the totalweight of the poly- 3,809,683 C6 Patented May 7, 1974 hydraxlne whereinx and y are as set forth above.

The dihydrazides useful in producing our novel polymers are well knownin the art and may be produced as set forth in Preparative Methods ofPolymer Chemistry, Sorensen et al., Interscience Publishers, 1961, pages91- 92, which publication is hereby incorporated herein by reference.

Examples of suitable dihydrazides which may be reacted according to theabove equation to produce our novel polymers include oxalic aciddihydrazide, succinic acid dihydrazide, glutaric acid dihydrazide,adipic acid dihydrazide, pimelic acid dihydrazide, suberic aciddihydrazide, azelaic acid dihydrazide, sebacic acid dihydrazide,undecanedioic acid dihydrazide, dodecanedioic acid dihydrazide,tridecanedioic acid dihydrazide, tetradecanedioic acid dihydrazide,pentadecanedioic acid dihydrazide, hexadecanedioic acid dihydrazide,heptadecanedioic acid dihydrazide, octadecanedioic acid dihydrazide,nonadecane dioic acid dihydrazide, eicosanedioic acid dihydrazide, andthe like.

The reaction is conducted without solvent at a temperature ranging fromabout 20 C. to about 275 C., preferably from about 235 C. to about 255C., at atmospheric through superatmospheric pressure of 1000 p.s.i.

The reaction should be allowed to proceed for from about 2 to about 15hours, preferably from about 5 hours to about 9 hours. After about thefirst 3 to 6 hours, the pressure is reduced to about p.s.i. primarilyfor reasons of safety and should not be considered critical to theprocess. After the reaction is allowed to run its course, the pressurevessel is vented and cooled. The polymers can be taken up in a solventsuch as methanol and cast into films.

The following examples are set forth for purposes of illustration onlyand are not to be construed as limitations on the present inventionexcept as set forth in the appended claims. All parts and percentagesare by weight unless otherwise specified.

Evaluation of copolymers Young female rabbits (2-5 months old) wereanesthetized with sodium pentothal. The fur was removed from theabdominal skin which was subsequently treated with Physohex andmethiolate. Two parallel incisions about A inch long were made 1 inchfrom each side of the midline of the abdomen. No more than seven pairsof incisions were made in each of four animals in any one series. Achannel was produced between the sets of incisions by the use of aseries of blunt forceps, such as the Kelly-Murphy variety. The testsample was drawn through the channel by means of one of theabove-mentioned forceps. The end of the film strip was secured bysuturing the ends of the channel with O0 silk.

At the end of the intermediate periods of 45 or 60 days and a terminaltesting period of 180 days, the animals were sacrificed and the area ofimplantation was exposed 4 What is claimed is: 1. A biodegradablefilm-forming copolymer having the ple. It seems reasonable to assumethat invasion precedes formula digestion and that invasion is anindication that absorption is more or less likely to occur within somedefinite period E of time, but may be too lengthy to be safe orpractical. N

On animals, where digestion occurred or was question- F/ l able or whereno sample could be found, dissections of the L\ jxJa LII II J L\ 1J6liver, kidney and spleen were taken and studied to deterb 9 any adverseresponse to the Polymer or Its degrada' wherein (1) x is a whole,positive integer of 0 6, inclutlohproducts' None l b l sive, (2) y is awhole, positive integer of 6-18, inclusive d was 3 :5 a i arp i etween g(3) the nitrogen content of the polymer ranges from about an g i 3% t ei 2 p0 2 was "I Serve 31.5% to about 35.5%, by weight, based on thetotal g 5 mince 3 co taxi} gfi as weight of the polymer, (4) a+c=b, (5)no a, b or c radiu y lgesp on y a lug-gray Scar me 0st.) was 0 cal isbonded to itself and (6) no a or c radical is bonded served. Thisphenomenon, WhlCh also occurs with catgut to each other resorption, isconsidered so characteristic of cellular re- 2 A copol'ymer according toclaim 1 wherein x is 4 sponse to an absorption process that it forms thebasis of y is 8 our evalution. 9

3. A co o1 mer accordm to claim 1 wherein x is 4 and Monomers A and Bare reacted under the conditlons 7 p y g specified 1n Table I, below.The pressure is reduced to 100 4' A copolymer according to claim 1wherein x is 3 p.s.i. after 4% hours and the resultant polymer is reandy is 7.

cotvlered 1n methanol. The results are set forth 1n the 5' A copolymeraccording to claim lwhemin xis 3 and ta e.

y 18 8. The hydrazine hydrate 1S p y 111 Order to 6. A copolymeraccording to claim 1 wherein at is 5 tain the reaction in one directioni.e. towards copolymer d y i 7,

formation which is necessary due to the by-product water 7. A copolymeraccording to claim 1 wherein x is 6 produced. and y is 7.

TABLE I Hydrazine Parts Polymer Hydra- Biodegradzine Mono- Mono- Temp.,C./p1essure, p.s.i./ Mole per- Mole per- Total ability Example Monomer AMonomer B hydrate mer A mer B time, hours cent A cent B percent N (180days) 1 SAMMI- Adipec 30.0 36.8 20.8 250/760/3 260/100/2 56.2 43.8 33.93Yes. 12.5 20.0 17.5 242/340/6 26 10 3 45.2 54.8 35. 21 Yes.

30 do 14261516 1.25 .48 4.12 250/163/4 275/128/2 9.5 90.5 30.88 NO.

Glutamn 1.25 .52 3.8 259/170/3 272+100/2 16.3 83.7 33. 38 Yes. Subrie-.Sebaelc.-. 2.5 4.38 4.79 261/365 4 270/100 214 51.0 49.0 31.30 NO.

Aze1eic 1.25 1.18 3.10 260/190/4 269/118/2 30.2 69.8 32. 82 Yes. .do1.25 1.25 3.19 258/175/4 207/117/2 29.6 70.4 31.87 Yes.

o 1.25 1.9 2.26 263/194/336 270/117/2 43.7 56.8 30.10 No. d0 .60 1.72243/80/4 255/40/2 50.0 50.0 31.08 No. Adipie .35 .60 .35 238//4 250/40/257.4 42.0 35.10 Yes. Sebaclc 2.5 2.05 6.76 263/250/M 270//2 32.7 67.334.13 Yes. Malonie Azeleic 1.25 .48 3.81 260/168/3 271//2 18.5 81.538.12 C Sebacic Sebaele 5.0 20.0 260/540/3% 270/100/2 50.0 50.0 28.80NO.

I C=Comparative. I Too water-soluble to ascertain.

References Cited UNITED STATES PATENTS 2,512,667 6/1950 Moncrieif 260-22,512,601 6/1950 Bates et al 260-78.4

JOSEPH L. SCHOFER, Primary Examiner J. KIGHT, Assistant Examiner US. Cl.X.R.

260-78 R, 78.4 R; 260Dig. 43

